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H5N1 Vaccines Being Prepared
 
 
  Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial
 
The Lancet Early Online Publication, 7 September 2006
 
Summary
Background

Avian influenza A virus H5N1 has caused widespread infections that have resulted in severe disease or death in poultry and wild birds as well as human beings. This virus has the potential to emerge as a pandemic threat and H5N1 vaccines are being developed in many countries. Our aim was to assess the safety and immunogenicity of an inactivated adjuvanted whole-virion H5N1 vaccine.
 
Methods
A stratified randomised, placebo-controlled, double-blind phase I clinical trial was done in 120 volunteers aged 18-60 years. Volunteers were assigned to receive two doses of placebo (n=24) or an inactivated whole-virion influenza A (H5N1) vaccine with 1-25 μg (24), 2-5 μg (24), 5 μg (24), or 10 μg (24) haemagglutinin per dose with aluminium hydroxide adjuvant on day 0 and 28. Serum samples were obtained on day 0, 14, 28, 42, and 56 for haemagglutination inhibition and virus neutralisation assays. This trial is registered with the ClinicalTrials.gov registry with the number NCT00356798.
 
Findings
All four formulations of vaccines were well tolerated. No serious adverse event was reported and most local and systemic reactions were mild and transient. All formulations induced antibody responses after the first dose; the highest immune response of 78% seropositivity was seen in the 10 μg group after two vaccine doses. Two individuals dropped out: one in the 1-25 μg group (withdrew consent) and one in the 10 μg group (discontinued); one individual was also excluded from the final analysis.
 
Interpretation
A two-dose regimen of an adjuvanted 10 μg inactivated whole-virion H5N1 vaccine met all European regulatory requirements for annual licensing of seasonal influenza vaccine. Lower doses of this vaccine could achieve immune responses equivalent to those elicited by adjuvanted or non-adjuvanted split-virion vaccines. The use of a whole virion vaccine could be more adaptable to the antigen-sparing strategy recommended by WHO for protection against an influenza pandemic.
 
Influenza pandemic vaccine candidates are being developed and clinically assessed by several vaccine manufacturers throughout the world.7 An early report about the clinical trials of a non-adjuvanted split-virion H5N1 vaccine produced by Sanofi Pasteur in the USA indicates that two high doses of vaccine (90 μg antigen per dose) were required to induce immune response in most recipients.9 Sanofi Pasteur in France have also reported their phase I clinical trial of a split-virion H5N1 vaccine adjuvanted with aluminium hydroxide.10 Their results showed that a two-dose regimen of 30 μg adjuvanted vaccine induced the highest level of immunity consistent with the European Union (EU) Committee for Medicinal Products for Human Use (CHMP) licensing criteria for interpandemic influenza vaccines. The findings of these and other studies suggest that a two-dose vaccination schedule and an adjuvant system will be required for a pandemic vaccine to elicit a satisfactory immune response in unprimed populations.11,12 Furthermore, whole-virion vaccine is suggested to be more immunogenic than conventional split-virion or subunit vaccines in naive populations.13-15
 
GSK reports significant advance in H5N1 pandemic flu vaccine programme
 
GSK Press Release, Issued: July 26th 2006, London, UK and Rixensart, Belgium: GlaxoSmithKline (GSK) plc today announced headline data showing that its H5N1 pandemic flu vaccine achieved a high immune response at a low dose of antigen. The vaccine, which uses a proprietary adjuvant, enabled over 80% of subjects who received 3.8μg of antigen to demonstrate a strong seroprotective immune response. This level of seroprotection meets or exceeds target criteria set by regulatory agencies for registration of influenza vaccines. Efficacy results at these levels of antigen dosage have also not been reported for any other H5N1 vaccine in development to date, including those using other adjuvants such as alum.
 
Commenting on the data, JP Garnier, GlaxoSmithKline's Chief Executive Officer, said: "These excellent clinical trial results represent a significant breakthrough in the development of our pandemic flu vaccine. This is the first time such a low dose of H5N1 antigen has been able to stimulate this level of strong immune response.
 
There is still a lot more work to be done with this programme, but this validation of our approach provides us with the confidence to continue developing the vaccine, including assessment of its ability to offer cross-protection to variants of the H5N1 strain. All being well, we expect to make regulatory filings for the vaccine in the coming months."
 
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The results were based on an interim analysis of a clinical trial conducted in Belgium which involved 400 healthy adults aged 18-60 years of age. The vaccine tested was produced from inactivated H5N1 virus and contained a novel, proprietary adjuvant. An adjuvant is an ingredient which stimulates the immune system and increases response to the vaccine. Trial participants were vaccinated twice during the course of the trial and four different levels of antigen dose were tested, with 3.8μg being the lowest dose assessed.
 
In this study, immune response was defined as the increase in the number of antibodies an individual produced in response to the vaccine. Levels of antibody protection were established through measurement of hemagglutination inhibition (HI), hemagglutination being the clumping together of red blood cells, which cannot occur when antibodies are present. HI is a standard efficacy measure used in the evaluation of influenza vaccines, and an individual with an HI titer of greater than 40 is considered to be protected, or to have "seroprotection." In this clinical trial, over 80% of subjects, who received 3.8μg of antigen with adjuvant, demonstrated a seroprotective immune response. GSK's adjuvanted investigational pandemic vaccine has not received marketing approval from any regulatory agency.
 
H5N1 vaccines: how prepared are we for a pandemic?
COMMENTARY

 
The Lancet Early Online Publication, 7 September 2006
 
Iain Stephenson
Infectious Diseases Unit, Leicester Royal Infirmary, Leicester LE1 5WW, UK
 
Highly pathogenic avian influenza (H5N1 strain) continues to cause outbreaks in poultry and migratory birds in Asia, Europe, and Africa. Since 2003, over 240 associated human infections (with 59% mortality) have been reported, with deaths in 2006 so far exceeding those in 2005.1 The A/H1N1 virus responsible for the 1918 pandemic was derived from an avian virus,2 and caused up to 50 million deaths. If pandemic H5 emerges, the consequences could be worse. Vaccination will be central to our response.
 
In today's Lancet, Jiangtao Lin and colleagues3 assess an alum-adjuvanted whole-virion H5N1 vaccine. Two doses containing 10 μg H5 haemagglutinin induced seroconversions in 78% and 96% of recipients by neutralising and haemagglutinin-inhibition responses, respectively. These findings identify a potential dose-sparing approach that could be crucial for a global supply of pandemic vaccine.
 
The development of vaccines against H5 viruses is challenging because these viruses are lethal to embryonated eggs, in which influenza viruses are grown for vaccine production.4 To generate suitable vaccine-reference strains, highly pathogenic viruses are engineered to remove the aminoacid sequence in the haemagglutinin responsible for virulence, and then combined with influenza viruses that grow well in eggs. The bulk material is inactivated and usually processed into split or subunit vaccines containing purified haemagglutinin.5
 
The calculation of a supply for a pandemic vaccine raises concerns. The global manufacturing capacity of trivalent seasonal influenza vaccine is 300 million doses every 6 months.6 If monovalent vaccine were similarly formulated, 15 μg haemagglutinin per dose, 900 million vaccines would be available. Because the population is non-immune and requires two doses, sufficient vaccine for 450 million people could be produced. Clinical studies of split H5N1 vaccines are disappointing. A US study of non-adjuvanted H5N1 vaccine found that only two doses containing 90 μg haemagglutinin per dose induced acceptable antibody levels.7 In France, two 30 μg doses of alum-adjuvanted H5N1 vaccine were immunogenic, with no effect of alum adjuvant at lower doses.8 So, within current manufacturing constraints of split vaccines, supplies of either of these two vaccines would be limited to 75 or 225 million people only. Worryingly, egg yields of antigen from engineered H5N1 viruses are 30-40% lower than the average of seasonal influenza viruses, reducing further the number of doses that would be available for clinical use. This situation falls far short of global requirements, but in the event of tomorrow's pandemic, is where we are today.
 
Lin and colleagues' findings are consistent with experience that whole-virion vaccines have better immunogenicity in immunologically naive individuals than split and subunit vaccines.4,8,9 Human H5N1 cases first occurred in 1997, and whole-virion vaccines were predicted to allow a dose-sparing approach, so why has evaluation taken so long? Manufacturers producing split seasonal vaccines cannot easily switch production to whole-virion approaches without adopting new processing methods that require additional infrastructure and impose regulatory, licensing, and commercial uncertainties. Although well tolerated in Lin and colleagues' study, earlier whole-virion vaccines were associated with febrile reactions, particularly in children.9,10 Careful investigation is needed before widespread immunisation; although with the potential disruption by pandemic influenza, modest reactogenicity might be acceptable.
 
Because of the antigenic diversity of current circulating H5N1 viruses,1 vaccine prepared from earlier strains and stockpiled by authorities might be poorly matched to an emergent pandemic virus. Effective adjuvants might overcome this problem. A trial of MF59-adjuvanted subunit H5N3 vaccine found a third dose induced cross-reactive antibodies to a range of H5N1 variants, suggesting that prepandemic priming of the population might be a useful strategy.11,12 Whether whole-virion vaccines can induce broad cross-reactive responses needs investigation. Because Lin and colleagues did not assess non-adjuvanted whole-virion vaccine, any immunopotentiating effect of alum cannot be determined.
 
Traditional haemagglutinin-inhibition assays for detection of anti-influenza antibody have known correlates of immune-protection and are used for vaccine licensure. However, they are considered generally insensitive for detection of anti-H5 antibody.11-13 Good haemagglutinin-inhibition titres were detected in Lin and colleagues' study, a finding that merits further investigation. As an alternative, neutralising antibody responses are commonly used to detect antibody to avian influenza.10-12 However, significant interlaboratory variability of assay endpoints, and lack of established correlates of immunity, create challenges for licensing. Development of international standards for assessing serological responses to H5N1 is crucial for comparative analysis of vaccine studies. Until these are available, postvaccination serum samples, or at least a subset, might be best analysed in a single laboratory.
 
Although vaccine manufacturing capacity has had substantial investment from industry, global production capacity remains insufficient to meet pandemic demands. The US administration has invested $1 billion to expand production sites there.14 European Union governments must also respond to the current threat. Although developments including cell-culture systems, live-attenuated vaccines, new adjuvants, and DNA approaches will be important in future planning, studies of dose-sparing vaccine formulations in children, adults, and elderly people should be international health priorities to optimise current immunisation strategies.
 
I have received grants for scientific research, speakers' honoraria, and sponsorship for travel to international meetings from drug companies who make influenza vaccines, including Novartis, GlaxoSmithKline, and Aventis-Pasteur.
 
 
 
 
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